PAC-1 is an orally active small-molecule procaspase-3 activator that induces cancer cell apoptosis with an EC50 of 2.08μM. PAC-1 can be used in the research of malignant tumors and hematologic cancers[1-4].
In vitro, PAC-1 (10–50μM) was added to HeLa cervical cancer cells for 15min, significantly reduced the intracellular free Zn²⁺ concentration, triggered endoplasmic reticulum (ER) Ca²⁺ release, and increased the cytoplasmic Ca²⁺ concentration. PAC-1 (25μM) was applied to U-937 lymphoma cells or HL-60 leukemia cells for 6h, significantly upregulating the expression of genes such as DDIT4, JUN, ATF3, and TNF, thereby inducing apoptosis. PAC-1 (100μM) was administered to U-937 lymphoma cells for 1–3h or to HeLa cells for 15–60min, which significantly induced ER stress and mitochondrial morphological speckling, downregulated TNF expression, and triggered cell death[5]. PAC-1 (1–30μM) was incubated with UMR106 osteosarcoma-like cells for 24h, significantly upregulating Fgf23 gene expression while reducing cell proliferation and viability[6].
In vivo, PAC-1 (0.15, 1.5, or 15nmol/site; single) was subcutaneously injected into the periorbital region of C57BL/6J mice. PAC-1 significantly induced dose-dependent and sustained periorbital mechanical allodynia[7]. PAC-1 (50mg/kg; once daily) was intraperitoneally injected into SCID or Balb/c nude mice bearing human breast cancer (MDA-MB-435), liver cancer (Hep3B), or gallbladder cancer (GBC-SD) xenografts for 30 days. PAC-1 significantly inhibited the in vivo growth of these tumors, which highly expressed procaspase-3[8].
References:
[1] Seervi M, Sobhan PK, Joseph J, et al. ERO1α-dependent endoplasmic reticulum-mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1). Cell Death Dis. 2013 Dec 19;4(12):e968.
[2] Putt KS, Chen GW, Pearson JM, et al. Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy. Nat Chem Biol. 2006 Oct;2(10):543-50.
[3] Rees TA, Labastida-Ramírez A, Rubio-Beltrán E. Calcitonin/PAC1 receptor splice variants: a blind spot in migraine research. Trends Pharmacol Sci. 2023 Oct;44(10):651-663.
[4] Rubio-Beltrán E, Correnti E, Deen M, et al. PACAP38 and PAC1 receptor blockade: a new target for headache? J Headache Pain. 2018 Aug 7;19(1):64.
[5] West DC, Qin Y, Peterson QP, et al. Differential effects of procaspase-3 activating compounds in the induction of cancer cell death. Mol Pharm. 2012 May 7;9(5):1425-34.
[6] Münz S, Feger M, Edemir B, et al. Up-Regulation of Fibroblast Growth Factor 23 Gene Expression in UMR106 Osteoblast-like Cells with Reduced Viability. Cells. 2021 Dec 23;11(1):40.
[7] De Logu F, Landini L, Janal MN, et al. Migraine-provoking substances evoke periorbital allodynia in mice. J Headache Pain. 2019 Feb 14;20(1):18.
[8] Wang F, Wang L, Zhao Y, et al. A novel small-molecule activator of procaspase-3 induces apoptosis in cancer cells and reduces tumor growth in human breast, liver and gallbladder cancer xenografts. Mol Oncol. 2014 Dec;8(8):1640-52.
PAC-1是一种具有口服活性的小分子procaspase-3激活剂，可诱导癌细胞凋亡，EC50为2.08μM。PAC-1可用于恶性肿瘤和血液系统癌症的相关研究[1-4]。
在体外，PAC-1（10–50μM）处理HeLa宫颈癌细胞15min，显著降低细胞内游离Zn²⁺浓度，触发内质网Ca²⁺释放及细胞质Ca²⁺浓度升高；PAC-1（25μM）处理U-937淋巴瘤细胞或HL-60白血病细胞6h，显著上调DDIT4、JUN、ATF3及TNF等基因的表达，诱导细胞凋亡；PAC-1（100μM）处理U-937淋巴瘤细胞1-3h或HeLa细胞15-60min，显著诱导内质网（ER）应激及线粒体形态斑点化，下调TNF等基因表达并引发细胞死亡[5]。PAC-1（1–30μM）处理UMR106骨肉瘤样细胞24h，显著上调Fgf23基因的表达，同时降低细胞增殖和活力[6]。
在体内，PAC-1（0.15、1.5或15nmol/site；单次）皮下注射于C57BL/6J小鼠的眼眶周区域。PAC-1显著诱导了剂量依赖性和持续性的眶周机械性异位痛[7]。PAC-1（50mg/kg；每日一次）腹腔注射于携带人类乳腺癌（MDA-MB-435）、肝癌（Hep3B）或胆囊癌（GBC-SD）异种移植物的SCID或Balb/c裸鼠30天。PAC-1显著抑制了这些高表达procaspase-3的肿瘤在体内的生长[8]。